This invention relates to treatment and control of pain by administering to a subject in need of such treatment or control an effective amount of loxapine or amoxapine, or of a substance that provides loxapine or amoxapine in the body. More particularly this invention relates to treatment or control of pain by systematically administering, for example by inhalation, loxapine, amoxapine, or a substance that provides loxapine or amoxapine in the body.
Loxapine [2-chloro-11(4-methyl-1-piperazinyl)dibenz(b,f) (1,4) oxazepine] is an antipsychotic drug particularly useful for treating schizophrenia or related psychotic conditions. It is commercially available in the form of a salt, typically the hydrochloride or succinate. Amoxapine [2-chloro-11(1-piperazinyl)dibenz(b,f) (1,4) oxazepine] is a known antidepressant that differs from other antidepressants in that it has both antidepressant and antipsychotic efficacy. Thus, amoxapine, unlike other antidepressants, is used mainly in treatment of psychotic depression.
Some patents and literature indicate that selected antipsychotics and/or antidepressant drugs may treat pain to a certain degree. However, data supporting these suppositions have been scattered and spotty, with some drugs showing some capability for controlling pain to varying degrees; whereas, other compounds from the same pharmacological class are completely ineffective in pain control. Thus, no real overall pattern emerges.
For example, U.S. Pat. Nos. 5,929,070, 5,945,416, and 6,258,807 disclose the use of olanzapine, alone or in combinations, to treat various types of pain. U.S. Pat. No. 6,444,665 discloses the use of several a typical antipsychotic compounds, namely risperidone, clozapine, quetiapine, sertindole, ziprasidone and zotepine, in treatment of pain especially when administered with a number of other pain-relieving drugs. On the other hand, another study [Schreiber et al., (1999) Pharmacology Biochemistry Behavior 64:75], documents that there are differences between a typical antipsychotics, even from the same class (e.g., olanzapine and clozapine), in their ability to control pain; and thereby demonstrates that analgesic effects are not a common class effect of antipsychotic medications.
U.S. Pat. No. 6,290,986 discloses transdermal administration of various drugs to control localized pain, in a special formulation comprising a lecithin organogel. Some antidepressant drugs are disclosed for use in such formulations, notably amitriptyline and doxepin. Those antidepressants are, however, claimed to be effective only in combination with guaifenesin, a compound known to have analgesic effects on its own, and there is no indication on the efficacy of the antidepressants when administered without guaifenesin. At the end of the patent text a “belief” is expressed that a number of other tricyclic drugs including amoxapine will show similar activity. In a later patent in the same series, U.S. Pat. No. 6,479,074, amoxapine is included in a list of tricyclic compounds that are said to be useful in some transdermal compositions for treating localized pain, again given in combination with guaifenesin. However, no data are reported for amoxapine. Similarly, U.S. Pat. No. 6,638,981 asserts that compositions containing antidepressants are effective in treating localized pain using topically applied compositions due to their local anesthetic effects. Analgesic effects of antidepressants after systemic administration, are, however, not suggested in that patent. Ten categories of antidepressants are mentioned, including a miscellaneous or “catch all” category. Each category includes a lengthy list of compounds supposedly having activity against pain. Amoxapine is listed among a number of other compounds in one of these categories but again no data are presented for it, or indeed for most of the compounds individually named in the patent. To the contrary, the data focus on two compounds—amitriptyline and ketamine. U.S. Pat. Nos. 5,900,249 and 6,211,171 also mention amoxapine in a list of compounds said to be useful in controlling pain when incorporated in topical compositions (e.g. as local anesthetics) but, yet again, no data are presented for amoxapine and no analgesic efficacy of antidepressants after systemic administration is suggested.
Lynch, [“Antidepressants as analgesics: a review of randomized controlled trials” (2001) Revue de Psychiatre et de Neuroscience 26:30], summarized the results of 59 randomized placebo-controlled trials examining the analgesic effect of antidepressants thus: “There is significant evidence that the tricyclic group of antidepressants is analgesic and that trazodone is not; the data regarding selective serotonin reuptake inhibitors are conflicting.” However, even in the case of tricyclic antidepressants, the list of 41 references involved work with only five such compounds (amitriptyline, doxepin, imipramine, clomipramine and desipramine) and did not include any reports for either loxapine or amoxapine, which differ significantly from the compounds tested in their mechanism of action.
In brief, a few antidepressants have been shown to have some analgesic properties, primarily when applied as topical or transdermal compositions, to control local pain or to provide local anesthesia. However, the effectiveness of these compounds is not related to their antidepressant activity and is not shown as representing any type of a class effect. Moreover, while another study [Hamon et al., (1987) Neuropharmacology 26: 531-539] showed that analgesic effects of morphine were enhanced after chronic treatment with amoxapine in an animal model, the results indicated that amoxapine itself had no effect on pain. FIG. 1 of that reference shows that there was no change in the latency of the tail-flick after chronic administration of amoxapine alone, thus indicating that amoxapine alone had essentially no effect on pain. In another reference, Pfeiffer [(1982) Geriatrics 27:67] states that some tricyclic antidepressants, including amoxapine, are “given with good results to patients who manifest pain as a somatization of depression”. Again, this is distinguishable in that these antidepressants are used to treat a somatization of depression that is manifested as pain, and not actual pain.
In short, amoxapine has been listed (in some of the above-mentioned patents) among a number of compounds that are believed to have some such activity, but no data are presented confirming that it has this capability, and one study showed a lack of such activity. Additionally, in contrast to references suggesting that the use of antipsychotics may reduce pain, some antipsychotics have been actually shown to produce the opposite effect, an increase in pain [see Frussa-Filho et al., (1996) Arch Int Pharmacodyn 331: 74-93 (haloperidol) and Gleeson et al. (1982). Psychopharmacology 78: 141-146 (chlorpromazine)]. Capability, if any, of amoxapine in controlling pain, particularly pain that is not localized, cannot be ascertained from this paucity of information, and there is no information in the art on whether loxapine would have any pain-controlling effect of any nature.